2-halo-4-nitroimidazole is a compound useful as an intermediate notably for the synthesis of various medicines or pesticides. In particular, it is useful as intermediate for the production of an antituberculous agent.
There is a need to develop efficient and economic methods for the production of these compounds.
NON-PATENT DOCUMENT 1 discloses a method for producing 1,4-dinitroimidazole by reacting 4-nitroimidazole in acetic acid with nitric acid. 1,4-dinitroimidazole is then extracted with the aid of dichloromethane. There is no disclosure as to how to produce 2-halo-4-nitroimidazole.
NON-PATENT DOCUMENT 2 discloses a synthesis of 1,4-dinitroimidazole by reacting nitroimidazole in glacial acetic acid with fuming nitric acid, followed by the addition of acetic anhydride. The resulting compound is then extracted from the solution with the aid of ethylene chloride. NON-PATENT DOCUMENT 2 also discloses a step of heating 1,4-dinitroimidazole at 120° C. to obtain 2,4-dinitroimidazole. There is no disclosure as to how to produce 2-halo-4-nitroimidazole.
PATENT DOCUMENT 1 discloses a process for the production of 2,4-dinitroimidazole. In a first step 1,4-dinitroimidazole is produced, by the reaction of 4-nitroimidazole in glacial acetic acid with nitric acid, in the presence of acetic anhydride. The compound is then precipitated and filtered. In a second step 2,4-dinitroimidazole is produced by heating 1,4-dinitroimidazole in chlorobenzene. The obtained yield can be calculated and is rather low (63%).
NON-PATENT DOCUMENT 3 discloses the preparation of 2,4-dinitroimidazole by thermal isomerization of 1,4-dinitroimidazole. The document also discloses (in relation to another reaction) the preparation of 2-chloro-4-nitroimidazole and 2-bromo-4-nitroimidazole by reacting 2,4-dinitroimidazole with respectively concentrated hydrochloric acid and concentrated hydrobromic acid under reflux. But the yields are rather low (2-chloro-4-nitroimidazole 67%; 2-bromo-4-nitroimidazole 30%).
PATENT DOCUMENT 2 discloses a method for the production of 2-chloro-4-nitroimidazole or 2-bromo-4-nitroimidazole comprising the iodination of 4-nitroimidazole and then the reduction of the obtained compound.
PATENT DOCUMENT 3 discloses a method for the production of 2-chloro-4-nitroimidazole comprising the reaction of 1-alkoxyalkyl-2-bromo-4-nitroimidazole with hydrogen chloride.
As for conventional production process of 2-chloro-4-nitroimidazole or 2-bromo-4-nitroimidazole, 1,4-dinitroimidazole (II) obtained by nitrating 4-nitroimidazole (I) was isolated and dried. Subsequently, 2,4-dinitroimidazole (III) obtained by thermal rearrangement of 1,4-dinitroimidazole (II) is isolated and dried, and finally 2,4-dinitroimidazole (III) is treated with hydrochloric acid or hydrobromic acid to obtain 2-chloro-4-nitroimidazole (IV) or 2-bromo-4-nitroimidazole (V) in the known synthetic processes.

As for a production process of 1,4-dinitroimidazole from 4-nitroimidazole, a production process of 2,4-dinitroimidazole from 1,4-dinitroimidazole, a production process of 2-chloro-4-nitroimidazole or 2-bromo-4-nitroimidazole from 2,4-dinitroimidazole, processes described in the following documents (PATENT DOCUMENT 1 and NON-PATENT DOCUMENTS 3 to 5) are known.
As a production process of 1,4-dinitroimidazole from 4-nitroimidazole, in NON-PATENT DOCUMENT 4,4-nitroimidazole is added to acetic acid and nitric acid having a specific gravity of 1.5 is added dropwise thereto, and then acetic anhydride is added to perform nitration reaction. Then the reaction solution is extracted with dichloromethane and the dichloromethane layer is washed with a saturated sodium hydrogen carbonate aqueous solution and dichloromethane is evaporated under reduced pressure to produce 1,4-dinitroimidazole at a yield of 71.5%.
In NON-PATENT DOCUMENT 5, 100 mass % nitric acid is added dropwise to 4-nitroimidazole in glacial acetic acid and acetic anhydride is further added dropwise thereto to perform nitration reaction, and then the reaction solution is added into crushed ice and 1,4-dinitroimidazole is produced at a yield of 52.1% by performing filtration, washing and vacuum drying.
In PATENT DOCUMENT 4, 98 mass % nitric acid is added dropwise to 4-nitroimidazole dissolved in glacial acetic acid and acetic anhydride is further added dropwise thereto to perform nitration reaction, and then the reaction solution is added into crushed ice and 1,4-dinitroimidazole is produced at a yield of 69.1% by performing filtration and drying.
In addition, as a production process of 2,4-dinitroimidazole from 1,4-dinitroimidazole, in NON-PATENT DOCUMENT 5, isolated and dried 1,4-dinitroimidazole is subjected to thermal rearrangement reaction in chlorobenzene at 115° C. and then the solution is concentrated and crystallized. Subsequently, crystals are filtered and vacuum dried at 60° C. or less to produce 2,4-dinitroimidazole at a yield of 87.5%.
In NON-PATENT DOCUMENT 3, isolated and dried 2,4-dinitroimidazole is refluxed with hydrochloric acid or hydrobromic acid to perform chlorination or bromination reaction, and 2-chloro-4-nitroimidazole and 2-bromo-4-nitroimidazole are produced respectively at a yield of 67% and 30%.
In PATENT DOCUMENT 4, isolated and dried 1,4-dinitroimidazole is subjected to thermal rearrangement reaction by heating in a range of 95 to 98° C. to produce 2,4-dinitroimidazole.
As for conventionally employed common processes for synthesizing 2-chloro-4-nitroimidazole, a process described in the following NON-PATENT DOCUMENT 3 is known.
In NON-PATENT DOCUMENT 3, after concentrated hydrochloric acid is added to 2,4-dinitroimidazole, the resultant solution is refluxed for 3 hours to perform chlorination reaction, and 2-chloro-4-nitroimidazole is produced at a yield of 67% by performing cooling, filtration and washing.
1,4-Dinitroimidazole is a substance widely used as intermediates of various medicinal drugs, agricultural agents and explosives. As for conventionally employed common processes for synthesizing 1,4-dinitroimidazole, processes described in the following documents (NON-PATENT DOCUMENTS 4 and 5, and PATENT DOCUMENT 1) are known.
In NON-PATENT DOCUMENT 4,4-nitroimidazole is added to acetic acid and nitric acid having a specific gravity of 1.5 is added dropwise thereto, and then acetic anhydride is added to perform nitration reaction. Then the reaction solution is extracted with dichloromethane, the dichloromethane layer is washed with a saturated sodium hydrogen carbonate aqueous solution and dichloromethane is evaporated under reduced pressure to produce 1,4-dinitroimidazole at a yield of 71.5%. Here, according to Kagaku Binran Kisohen II edited by The Chemical Society of Japan, the concentration in term of mass % of the nitric acid having a specific gravity at 25° C. of 1.5 is in a range of 82 to 100 mass % when rounding off the hundredth number of the specific gravity. According to this, it can be understood that the concentration of the nitric acid used in NON-PATENT DOCUMENT 4 is in a range of 82 to 100 mass %.
In NON-PATENT DOCUMENT 5, 100 mass % nitric acid is added dropwise to 4-nitroimidazole in glacial acetic acid and acetic anhydride is further added dropwise thereto to perform nitration reaction, and then the reaction solution is added into crushed ice and 1,4-dinitroimidazole is produced at a yield of 52.1% by performing filtration, washing and vacuum drying.
In PATENT DOCUMENT 1, 98 mass % nitric acid is added dropwise to 4-nitroimidazole dissolved in glacial acetic acid and acetic anhydride is further added dropwise thereto to perform nitration reaction, and then the reaction solution is added into crushed ice and 1,4-dinitroimidazole is produced at a yield of 69.1% by performing filtration and drying.
As for conventional processes for nitrating imidazole (I) to obtain 4-nitroimidazole (II), processes described in the following documents (NON-PATENT DOCUMENTS 4 and 5) are known.
In NON-PATENT DOCUMENT 4, nitric acid is added to imidazole at 30 to 40° C., and then concentrated sulfuric acid is added dropwise to this solution while the solution is ice-cooled and the temperature is elevated to 75° C. and the solution is stirred for 1 hour. Then the solution is cooled and a mixed solution of nitric acid and concentrated sulfuric acid is added thereto. The solution is heated and stirred for another hour and the reaction liquid is poured into ice and 4-nitroimidazole is produced at a yield of 73% by performing filtration, washing and drying.
In NON-PATENT DOCUMENT 5, after imidazole is dissolved in nitric acid, the resultant solution is cooled to 0 to 5° C. and concentrated sulfuric acid is added dropwise thereto. After this solution is refluxed for 2 hours, the solution is cooled to room temperature and then poured into ice, and 4-nitroimidazole is produced at a yield of 60% by performing filtration, washing and drying.